Project Summary/Abstract It is now well-recognized that cardiovascular disease (CVD) has many features of a systemic inflammatory process, and recent studies suggest that CVD can be viewed as a state of defective resolution of inflammation. Eicosanoids are diet-derived bioactive lipid metabolites of polyunsaturated fatty acids (PUFAs, e.g. omega-3 and omega-6 fatty acids), and have been implicated as upstream drivers of inflammatory conditions including CVD. Eicosanoids can both promote inflammation (pro-inflammatory eicosanoids) or reverse it (anti-inflammatory eicosanoids). The balance of these pro- and anti-inflammatory eicosanoids is critical for the clinical manifestation of inflammation, and therefore are tightly regulated via cellular signaling pathways. A major gap in our knowledge is how specific eicosanoid mediators drive the CVD-associated inflammation in humans, and conversely, how other eicosanoids promote its resolution. Recent advances in high performance mass spectrometry technology now allow the accurate identification and quantification of more than 150 distinct eicosanoids and related PUFA species circulating in human plasma. The proposed study will evaluate a comprehensive panel of pro- and anti-inflammatory eicosanoids in relation to cardiovascular risk factors and clinical events, as well as assess how diet, drugs, and genetic variants modulate the delicate balance of eicosanoids. This will be conducted within two large-scale prospective clinical trials, the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and the VITamin D and OmegA-3 TriaL (VITAL). We will leverage banked blood specimens and collected clinical trial data from 3,550 men and women (1,275 incident CVD events) to examine eicosanoids in relation to CVD risk factors and events. In Aim1 we will focus on the JUPITER trial of participants recruited based on the presence of chronic systemic inflammation to examine the associations (cross-sectional and change over time) of pro-and anti-inflammatory eicosanoids with CVD risk factors and events, and assess changes in eicosanoid levels with high-intensity statin therapy versus placebo. In Aim 2, we will replicate the JUPITER analyses in the VITAL trial, an independent population of older healthy individuals (20% African Americans). In VITAL, we will assess eicosanoid associations with CVD risk factors and incident events, and effects of marine omega-3 fatty acid supplementation versus placebo, then we will perform meta-analysis of the JUPITER and VITAL studies. We will also assess whether the benefits of the interventions differ based on levels of eicosanoids, and how they are modulated by genetic variants in enzymes involved in eicosanoid pathways. This comprehensive approach may elucidate specific pro- and anti-inflammatory PUFA derived eicosanoids associated with CVD, and could trigger therapeutic anti-inflammatory approaches that are in line with personalized medicine.